Organic amide compounds derived from nitrogenous lipids

ABSTRACT

Organic amide compounds of the formula ##STR1## wherein R 1  --CO is a residue of a carboxylic acid with the proviso that the carboxylic acid is not a natural fatty acid normally bound to nitrogen of nitrogenous lipids, R 2  is a hydrogen atom, a C 1-7  alkyl group, or a C 4-7  cycloalkyl group, and R 3-N  is a residue of a nitrogenous lipid. The compounds are useful in increasing or stimulating the in vivo biological activity of in vitro biologically active carboxylic acids.

This application is a divisional of application Ser. No. 807,841, filedon Dec. 11, 1985, which is a Continuation of Ser. No. 404,706, filed onAug. 3, 1982, now abandoned.

BACKGROUND AND FIELD OF THE INVENTION

The present invention relates to novel organic amide compounds,procedures for preparing the compounds, pharmaceutical compositionscontaining the same and methods for using the compounds. These novelorganic amides are primarily comprised of a carboxylic acid moiety and anitrogenous lipid moiety.

Numerous compounds are known to be active in vitro and yet exhibitlittle or no activity in vivo. In particular, numerous carboxylic acidsare known to be important in the actions of the peripheral and centralnervous systems and are active in vitro but are either non-active oronly slightly active in vivo. Gamma-aminobutyric acid (GABA), forexample, is known to be active on the central nervous system in vitroand has been suggested as a possible inhibitory transmitter (Louis S.Goodman and Alfred Gilman, The Pharmacological Basis of Therapeutics,4th Ed., p. 429 (1970)). However, GABA has been found to be ineffectivewhen administered in vivo as measured by convulsion tests in mice.

The present inventors have found that compounds of the formula I,prepared by combining a carboxylic acid, such as GABA, with anitrogenous lipid, such as a phospholipid or sphingosine, provide amidecompounds which are active in vivo, exhibiting activities far superiorto that of the corresponding carboxylic acid or lipid compoundsadministered alone. For example, the amide of GABA with a sphingosineprovides a compound which is far more active in vivo than is GABA alone.Similarly, lysergic acid, dihydrolysergic acid and isolysergic acid areessentially inactive when administered alone, but when combined with asphingosine provide compounds of the formula I which have significant invivo activity as measured by hypoprolactinemic effects in rats.

The significantly improved pharmacological properties of the compoundsof formula I are thought to result from the ability of these compoundsto penetrate the hematoencephalic barrier and/or reach the peripheralorgans far better than the carboxylic acid compounds alone. This abilityof the compounds of the present invention favors the interaction betweenthe biologically active compound, such as the carboxylic acid, and thesitus of the specific interactions present in the membranes.

Hence, the compounds of the present invention are useful for enhancingor increasing the in vivo biological activity in vitro biologicallyactive carboxylic acids as well as stimulating the in vivo biologicalactivity of in vitro biologically active carboxylic acids which havelittle or no in vivo activity.

OBJECTS AND SUMMARY OF THE INVENTION

It is another object of the present invention to provide compounds whichpermit the in vivo activity of other compounds which are known to bebiologically active in vitro.

It is a further object of the present invention to provide a process forpreparing the novel amide compounds.

It is still another object of the present invention to provide methodsfor use the compounds of the present invention as therapeutic agents.

It is a still further object of the present invention to providepharmaceutical compositions which comprise at least one of the novelamide compounds as an active ingredient.

These and further objects of the present invention are accomplished byproviding the novel amide compounds of formula I and pharmaceuticalcompositions containing the same. These amide compounds comprise acarboxylic acid moiety and a nitrogenous lipid moiety and arepharamcologically active in vivo due to the activity of thecorresponding carboxylic acid but exhibit activity far superior thanresults from in vivo administration of the carboxylic acid alone.

DETAILED DESCRIPTION OF THE INVENTION

The novel organic amide compounds of the present invention arerepresented by the formula I ##STR2## wherein R₁ --CO is a residue of anorganic carboxylic acid which has a pharmaceutical or biologicalactivity with the proviso that the carboxylic acid is not a naturalfatty acid normally bound to nitrogen of nitrogenous lipids, R₂ is ahydrogen atom or one of a group of hydrocarbons and NR₃ is a residuederived from a nitrogenous liquid. Natural fatty acids normally bound tonitrogen in nitrogenous lipids are described in, for example, Wiegandt,Adv. in Lipid Res., Vol. 9, pp. 249-288, Ed. by Paoletti and Kritchezsky(Academic Press, 1971) and Ansell and Hawthorne, Phospholipids, Biochem.Biophys. Acta. Library, Vol. 3, pp. 420-425 (Elsevier Pub. Co., 1964).

The R₁ --COOH acids which give rise to the R₁ --CO residue are primarilythose acids which are fundamentally important to the peripheral andcentral nervous systems, such as lysergic, isolysergic, dihydrolysergic,2-bromolysergic, 2-bromo-dihydrolysergic, 1-methyllysergic,1-methyldihydrolysergic, 1-methyl-2-bromo-lysergic,1-methyl-2-bromodihydrolysergic, gamma-aminobutyric, valproic(2-propylpentanoic), trimethoxybenzoic, nicotinic, isonicotinic,picolinic and theophyllineacetic acids. These acids have the commonpharmaceutical characteristic of being active in vitro but nonactive oronly slightly active in vivo.

R₂ may be a hydrogen atom or a hydrocarbon, especially a saturatedaliphatic hydrocarbon or a saturated cycloaliphatic hydrocarbon group;for example an alkyl having from 1 to 7 carbon atoms such as butyl,isobutyl, tertiarybutyl, propyl, isopropyl, ethyl, and methyl or acycloalkyl having from 4 to 7 carbon atoms, such as cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl.

The --N--R₃ residue is derived from a nitrogenous lipid, especially fromphospholipids and sphingolipids. Phospholipids, natural products thatcan be extracted from bovine brain tissue, are chemically derived fromL-α-glycerophosphoric acid. (Lees, M. B., Met. Enzymol, Vol. 3, pp.328-345 (1957); Bigon et al, G. Brit. J. Pharmacol., Vol. 67, pp.611-619 (1979); Spanner, Form and Function of Phospholipids, Ed. byAnsell et al, Biochem. Biophys. Acta. Library, Vol. 3, pp. 43-65(1973)). The two major phospholipid groups which are utilized are thephosphatidylethanolamines (II) and the phosphatidylserines (III)represented by the following structures: ##STR3## wherein R and R'represent a hydrogen atom or the residue of an organic carboxylic acid,especially, the residue of a saturated or unsaturated fatty acid.

Sphinolipids are natural products extracted, in particular, from animalsand vegetables and contain an amino-alcohol moiety (Dawson, Form andFunction of Phospholipids, Ed. by Ansell et al, Biochem. Biophys. Acta.Library, Vol. 3, pp. 104-105 (1973); Kaller, Biochem. Zeitschrift, Vol.334, pp. 451-456 (1961); Sweeley et al, J. Lipid, Res., Vol. 1, pp.40-47 (1959); Radin, Lipids, Vol. 9, pp. 358-360 (1970)). Especiallypreferred sphinogosines are those having an average of 12 to 22 carbonatoms.

The sphingolipid derivatives which permit the preparation of thecompounds (I) of the present invention contain a sphingosinic residueand contain a free sphingosine --NH₂ group. Principally these are:

Sphingosine represented by the formula: ##STR4## wherein n may be from 6to 16, Dihydrosphingosine represented by the formula: ##STR5## wherein nmay be from 8 to 18, Psychosine or galactosylsphingosine represented bythe formula: ##STR6## wherein n may be from 6 to 16, Dihydropsychosinerepresented by the formula: ##STR7## wherein n may be from 8 to 18,Phosphorylcholine sphingosine or lisosphingomyelins represented by theformula: ##STR8## wherein n may be from 6 to 16,Phosphorycholine--dihydrosphingosine, or lisodihydrosphingomyelinesrepresented by the formula: ##STR9## wherein n may be from 8 to 18,Phytosphingosine represented by the formula: ##STR10## wherein n may befrom 11 to 15, and all other sphingolipids which through hydrolysis arecapable of releasing an amine (--NH₂) group, such as is indicated belowby the sphingomyelin formula XI: ##STR11##

Preparation Procedures

The organic amides (I) according to the present invention can beprepared according to a variety of preparation methods under conditionswhich prevent the esterification of the free hydroxy acid. Of all themethods which have proved to be particularly appropriate, the followingare most preferred.

1. The reaction between the R₁ CON₃ azides (corresponding to the R₁--COOH acid) and the nitrogenous lipid derivatives. The preparation ofthe R₁ CON₃ azides can be realized by utilizing one of the knownmethods.

2. The acylimidazole preparation method comprising reacting the R₁ COOHacid with N, N'-carboxydiimidazole, followed by the reaction of the thusproduced acylimidazole with the nitrogenous lipid.

3. The mixed anhydride preparation method comprising reacting the R₁COOH acid and trifluoroacetic acid anhydride to form a mixed anhydrideand then reacting the mixed anhydride with the nitrogenous lipid.

4. Preparing the acid chloride of the R₁ COOH acid followed by reactingthe acid chloride with the nitrogenous lipid.

5. Direct reaction between the R₁ COOH acid and the nitrogenous lipid inthe presence of a carbodiimide (for example dicyclohexylcarbodiimide,benzylisopropylcarbodiimide or benzylethylcarbodiimide) or anothersubstance similar to 1-hydroxybenzotriazole.

6. Direct condensation from heating the R₁ COOH acid with thenitrogenous lipidic derivatives.

7. Direct reaction between the methyl ester of the R₁ COOH acid and thenitrogenous lipidic derivative; this reaction is favored by heating.

8. Preparation of an ester by the reaction between an R₁ COOH acid and aphenol (for example, paranitrophenol) followed by the reaction of theester with the nitrogenous lipid. The ester preparation between the acidand a phenol can be realized by using one of the known methods.

In the preparation of the products described in formula (I) derived fromgamma-aminobutyric acid, the method preferably used is that consistingof the initial preparation of a gamma-aminobutyric derivative where theamine group is attached to a protective group, as for example, aphthaloyl or benzyloxycarbonyl group. The derivative thus prepared isthen further condensed with the nitrogenous lipid using one of thereactions previously described. The protective group is then eliminatedby means of an appropriate reaction and the product (I) is thusobtained. For example, if the protective group is phthaloyl, this groupcould be eliminated by hydrazinalysis.

The compounds of formula I, wherein the R₁ --COOH acid contains a basicgroup (for example, gamma-aminobutyric, nicotinic, lysergic ordihydrolysergic acid), can be salified with therapeutically used acidssuch as: hydrochloric, hydrobromic, methanesulphonic and malic acids.

As described above, according to the present invention, numerouscompounds, particularly carboxylic acids, can be combined withnitrogenous lipids to produce amine compounds which are pharmaceuticallyactive in vivo. Although not limiting, the following examples illustratethe products, preparation procedures and pharmaceutical preparations ofthe present invention.

EXAMPLE 1 Product 1

Gamma-aminobutyrylsphingosine amides of the formula: ##STR12## a. Agamma-phthalmid-butyryl-sphingosine-amide (Product 1a) is prepared asfollows: 5.7 g of sphingosine (obtained from the sphingolipids presentin the bovine brain and corresponding to a sphingosine C₁₈) are treatedwith 50 ml of absolute ethanol. 8.9 g of the para-nitrophenylester ofgamma-phthalmidbutyric acid (prepared according to: J. Org. Chem. 27,684-696, 1962) are added to the solution.

The solution is then heated and left to precipitate for 2 hours and thesolvent is vacuum separated. The residue is mixed with 500 ml of amethylene chloride ethanol mixture (4:1). The organic solution is washedwith an aqueous solution of sodium carbonate and then with water. Theorganic solution is dried on sodium sulphate, filtered and the solventis then vacuum separated.

The residue crystallizes from methylene chloride--n-hexane, M.P. 97° C.,yield 7.3 g.

Thin layer chromatography (silica gel) using a eluent mixture ofmethylene chloride:ethyl acetate:methanol, 70:30:10, indicates that itis a single compound with Rf of 0.4.

Elementary analysis gives the following results (%):

C 70.20; H 8.94; N 5.61

For C₃₀ H₄₆ N₂ O₄, theoretical % calculated is

C 70.00; H 9.01; N 5.44

b. 5.14 g of the gamma-phthalamid-butyryl sphingosineamide (Product 1a)are treated with 30 ml of absolute ethanol; 20 ml of an ethanolicsolution of 1 Molar hydrazine are added and heated and allowed toprecipitate for 2 hrs. The solvent is then evaporated in a vacuum and 50ml of acetic acid (2 Normal) is added to the residue and heated for 10minutes at 50° C. The mixture is left to cool to room temperature andfiltered. The filtered solution is concentrated in vacuum and a watersolution of NaOH (2N) until a clearly alkaline pH is obtained.

The aqueous phase is extracted with a mixture of methylene chloride:ethanol (4:1). The organic solution is dried on sodium sulphate, whichis filtered and evaporated. The residue crystallizes fromtertiarybutylmethyl ether, and gamma-amino-butyryl-sphingosine amides(Product 1) M.P. 87° C., are thus obtained (yield 3.1 g).

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water:ammonia concentrated aqueous solution(70:35:5:1) indicates that the Product 1 is a single compound with Rf of0.16.

Elementary analysis gives the following results (%):

C 68.56; H 11.50; N 7.37

For C₂₂ H₄₄ N₂ O₃, theoretical % calculated is

C 68.70; H 11.53; N 7.28

EXAMPLE 12 Products 2.1 and 2.2

Isolisergylsphingosine amides of the formula: ##STR13## andlysergylsphingosine amides, an isomer from the formula 2.1, of theformula: ##STR14## 6.7 g of D-lysergic acid are treated with 400 ml ofdimethylformamide (DMF) (this reaction is conducted taking care to workaway from light); the lysergic acid gradually forms a solution. 4.45 gof N,N'-carbonyl diimidazole dissolved in 125 ml of DMF are added to thesolution and the kept at room temperature for 2 hours. 8.25 g ofsphingosine (obtained from the sphingolipids present in the bovine brainand corresponding to a sphingosine C₁₈) are added and the mixture ismaintained at room temperature for 24 hours.

DMF is evaporated in vacuum and the residue is treated with 1000 ml ofethyl acetate, the suspension is filtered and the organic solutionwashed with 5M of ammonia and then with water. The organic solution isdried o sodium sulphate, and then filtered and evaporated, thusobtaining a residue.

The residue is then chromatographically fractionated, separating the twocompounds: Product 2.1; Product 2.2.

a. Product of 2.1-Isolysergylsphingosine-amide

Chromatography on silica gel plates using an eluent mixture of ethylacetate: methanol, 80:20, indicates that it is a single compound with Rf0.74. Evaluation of the specific rotating power is carried out inmethanol solution (1%) using a ldm polarimetric tube- result is (α)_(D)=235°

Elementary analysis gives the following results:

C 74.16; H 9.55; N 7.78

For C₃₄ H₅₁ N₃ O₃ % calculated is

C 74.27; H 9.35; N 7.64

b. Product 2.2-Lysergylsphingosine-amide (crystallizes from acetone,M.P. 139° C.)

Chromatography on silica gel plate using an eluent mixture of ethylacetate: methanol, 80:20, indicates that it is a single compound with Rf0.30. Evaluation of the specific rotary power is carried out in 1%chloroform using a 1 dm polarimetric tube-result is (α)_(D) =+3

Elementary analysis gives the following results (%):

C 74.10; H 9.42; N 7.80

For C₃₄ H₅₁ N₃ O₃ theoretical % calculated is

C 74.27; H 9.35; N 7.64

EXAMPLE 3 Product 3

a. Dihydrolysergylsphingosine amide of the formula: ##STR15## 2.7 g ofdihydrolysergic acid (prepared from catalytic hydrogenation of thelysergic acid) and 2.7 g of 1-hydroxybenzotriazole are added to 100 mlof chloroform. The mixture, under continual agitation, is brought to 30°C., after which 3 g of sphingosine (obtained from the sphingolipidspresent in the bovine brain and corresponding to a sphingosine C₁₈) and2 g of dicyclohexylcarbodiimide are added.

The mixture is heated and allowed to precipitate for 1 hour, brough toroom temperature and then 25 ml of ethanol are added.

The organic solution is washed with 5M ammonia and then with water. Theorganic solution is vacuum dried, thus obtaining a residue andsolubilized in 30 ml of methanol.

The methanolic solution is brought to 0°, thus precipitating thedicyclphexylurea; the suspension is filtered and the solvent iseliminated from the filtered substance by vacuum. The residue issolubilized by heating with 45 ml of acetone. While cooling, thedihydrolysergylsphinogosine amides crystallize, M.P. 206° C., yield 3.8g.

Thin layer chromatography (silica gel) using an eluent mixture ofmethylene chloride:ethyl acetate:methanol 60:30:15, indicates that it isa single compound with Rf of 0.25.

Evaluation of the specific rotary power is carried out in a 2% methanolsolution using a 1 dm polarimetric tube-result is (α)_(D) =-63°

Elementary analysis gives the following results (%):

C 73.85; H 9.72; N 7.34

For C₃₄ H₅₃ N₃ O₃ theoretical % calculated is

C 74.00; H 9.68; N 7.26.

b. The preparation of the salt with methane sulphonic acid from thedihydrolysergyl sphingosine amide is as follows: 1 g of dihydrolysergylsphingosine amide is dissolved in 50 ml of acetone, and 0.18 g ofmethane sulphonic acid are added. The solution is then concentrated insmall volumes, crystallizing the salt of the dihydrolysergylsphingosineamides with methane sulphonic acid.

Evaluation of the specific rotary power is carried out in a methanolsolution of 2% using a 1 dm polarimetric tube-result is (α)_(D) =-41.5°.

EXAMPLE 4 Product 4

Valproylsphingosine amide of the formula: ##STR16## 11.5 g ofsphinngosine (taken from the sphingolipids present in the bovine brainand corresponding to a sphingosine C₁₈) are treated with 1000 ml ofabsolute ethanol. To this solution 13.1 g of the para-nitrophenylesterof valproic acid (prepared according to: Chim. Ther. 3, (5), 336-42,1968) is added.

This solution is then treated in the manner described in Example 5. Theresidue is crystallized by tertiarybutyl methyl ether, M.P. 118° C.,yield 14.9 g.

Thin layer chromatography (silica gel) utilizing an eluent mixtureformed from: methylene chloride (70); ethyl acetate (30);methanol (10);indicates that it is a single compound with Rf 0.85.

Elementary analysis gives the following results (%):

C 73.30; H 12.25; n 3.11

For C₂₆ H₅₁ NO₃ theoretical % calculated is

C 73.36; H 12.08; N 3.29

EXAMPLE 5 Product 5

3,4,5-Trimethoxybenzoylsphingosine amide of the formula: ##STR17## 5 gof sphingosine (taken from the sphingolipids present in the bovine brainand corresponding to a sphingosine C₁₈) are treated with 500 ml ofabsolute ethanol. To this solution 7.35 g of a p-nitrophenylester of the3,4,5-trimethoxybenzoic acid are added (prepared according to: AnalesAsoc. Guim. Argentina 26, 51-56, 1938). This mixture is heated and leftto precipitate for 2 hours and the solvent is vacuum separated. Theresidue is mixed with 500 ml of a methylene chloride:ethanol mixture(4:1). The organic solution is washed with an aqueous solution of sodiumcarbonate and then with water. The organic solution is dried on sodiumsulphate, filtered and the solvent is then vacuum separated. The residuecrystallizes from tertiarybutyl methyl ether, M.P. 130° C., yield 7.3 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bymethylene chloride:ethyl acetate:methanol (40:30:10) indicates that itis a single compound with Rf of 0.5.

Elementary analysis gives the following results (%):

C 68.01; H 9.78; N 2.67

For C₂₈ H₄₇ NO₆ theoretical % is calculated is

C 68.12; H 99.60; N 2.84

EXAMPLE 6 Product 6

Theophyllinacetylsphingosine amide of the formula: ##STR18## 6 g ofsphingosine (taken from the sphingolipids present in the bovine brainand corresponding to a sphingosine C₁₈) are treated with 500 ml ofabsolute ethanol. To this solution are added 9.5 g of ap-nitrophenylester of theorphllineacetic acid (prepared according to:Annalen (1976) 860-75). The same procedure as described in Example 5 isthen followed.

The residue crystallizes from methanol, M.P. 189° C., yield 8.5 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bymethylene chloride:ethyl acetate; methanol (60:30:20), indicates that itis a single compound with Rf of 0.6.

Elementary analysis gives the following results (%):

C 62.31; H 8.70; N 13.30

For C₂₇ H₄₅ N₅ O₅ theoretical % calculated is

C62.40; H 8.73; N 13.48

EXAMPLE 7 Product 7

Nicotinylsphingosine amide of the formula: ##STR19## 5 g of sphingosine(obtained from the sphingolipids present in the bovine brain andcorresponding to a sphingosine C₁₈) are treated with 500 ml of absoluteethanol. 5.5 g of p-nitrophenylester of the nicotinic acid are added tothe solution (prepared according to: J. Chem. Soc. B (1971) 2401-6). Thesame procedure as described in Example ;b 5 is then followed.

The residue crystallizes from tertiarybutyl methyl ether, M.P. 105° C.,yield 6.7 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bymethylene chloride:ethyl acetate:methanol (70:30:10) indicates that itis a single compound with an Rf of 0.23.

Elementary analysis gives the following results (%):

C 71.12; H 9.78; N 6.70

For C₂₄ H₄₀ N₂ O₂ theoretical % calculated is

C71.24; H 9.97; N 6.92

EXAMPLE 8 Product 8

3,4,5-Trimethoxybenzoylpsycosine amide of the formula ##STR20## 5 g ofpsycosine (taken from the sphingolipids present in the bovine brain andcorresponding to a sphingosine C₁₈) are treated with 4.8 g of thep-nitrophenylester of trimethoxybenzoic acid in an ethanolic solution(see Example 5). The same procedure as described in Example 5 is thenfollowed.

The residue crystallizes from ethanol-acetone, M.P. 135° C., yield 6.7g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (110:40:6) indicates that it is a singlecompound with Rf of 0.85.

Elementary analysis gives the following results (%):

C 62.02; H 8.54; N 1.99

For C₃₄ H₅₇ NO₁₁ theoretical % calculated is

C 62.27; H 8.76; N 2.14

EXAMPLE 9 Product 9

Nicotinylpsycosine amide of the formula ##STR21## 5 g of psycosine(obtained from the sphingolipids present in the bovine brain andcorresponding to a sphingosine C₁₈) are treated with 3.5 g of thep-nitrophenylester of nicotinic acid in an ethanolic solution (seeExample 7). The same procedure as described in Example 5 is thenfollowed.

The residue crystallizes from acetone, M.P. 140° C., yield 6.7 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (110:40:6), indicates that it is a singlecompound with an Rf of 0.80.

Elementary analysis gives the following results (%):

C 63.30; H 8.75; N 4.80

For C₃₀ H₅₀ N₂ O₈, theoretical % calculated is

C 63.58; H 8.80; N 4.94

EXAMPLE 10 Product 10

3,4,5-Trimethoxybenzoyl-sphingosinephosphorylcholine amide of theformula ##STR22## 5 g of sphingosinephosphorylcholine (taken from thesphingolipids present in the bovine brain and corresponding to asphingosine C₁₈) are treated with 4.6 g of a p-nitrophenylester of the3,4,5-trimethoxybenzoic acid in an ethanolic solution (see Example 5).

The same procedure as described in Example 5 is then followed. Theresidue crystallizes from tertiarybutyl methyl ether, M.P. 127° C.,yield 6.1 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (60:35:8), indicates that it is a singlecompound with an Rf of 0.25.

EXAMPLE 11 Product 11

3,4,5-Trimethoxybenzoyl-phosphatidylserine amide of the formula##STR23## 5 g of phosphatidylserine (taken from the phospholipidspresent in the bovine brain and in which the groups R and R' are mainlystearic, palmitic, oleic, linolenic, linoleic and arachidonic acidresidues) are treated with 2.8 g of a p-nitrophenylester of3,4,5-trimethoxybenzoyl acid in an ethanolic solution (see Example 5).The same procedure as described in Example 5 is then followed, excludingthe wash of the organic solution with Na₂ CO₃. The residue is purifiedby chromatography, yield 4.5 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (70:30:5), indicates that it is a singlecompound with an Rf of 0.5.

EXAMPLE 12 Product 12

Nicotinylphosphatidylserine amide of the formula ##STR24## 5 g ofphosphatidylserine (taken from the phospholipids present in the bovinebrain and in which the groups R and R' are mainly stearic, palmitic,oleic, linolenic, linoleic and arachidonic acid residues) are treatedwith 2 g of a p-nitrophenylester of nicotinic acid in an ethanolicsolution (see Example 7).

The same procedure as described in Example 5 is then followed, excludingthe wash of the organic solution with Na₂ CO₃. The residue is purifiedby chromatography, yield 5.1 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (70:35:5), indicates that it is a singlecompound with an Rf of 0.5.

EXAMPLE 13

Product 13

3,4,5-Trimethoxybenzoyllisophosphatidylserine amide of the formula##STR25## 5 g of lisophosphatidylserine (taken from the enzymatichydrolysis of phosphatidylserine, the R group in thelisophosphatidylserine being mainly stearic or oleic acid) are treatedwith 4.3 g of a p-nitrophenylester of 3,4,5-trimethoxybenzoyl acid in anethanolic solution (see Example 5). The same procedure as described inExample 5 is then followed, excluding the wash of the organic solutionwith Na₂ CO₃. The residue is purified by chromatography, yield 6.0 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:water (60:35:8), indicates that it is a singlecompound with an Rf of 0.3.

EXAMPLE 14 Product 14

3,4,5-Trimethoxybenzoylphosphatidylethanolamine amide of the formula##STR26## 5 g of phosphatidylethanolamine (taken from the phospholipidspresent in the bovine brain and in which the groups R and R' are mainlyoleic, stearic, palmitic, linoleic and arachidonic acid residues) aretreated with 3 g of a p-nitrophenylester of 3,4,5-trimethoxybenzoyl acidin an ethanolic solution (see Example 5). The same procedure asdescribed in Example 5 is then followed. The residue is purified bychromatography, yield 5.1 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bymethylene chlorine:ethyl acetate:methanol (70:30:20), indicates that itis a single compound with an Rf of 0.30.

EXAMPLE 15 Product 15

Dihydrolysergyldihydrosphingosine amide of the formula ##STR27##

The procedure is carried out as described in Example 3, beginning with2.5 g of dihydrosphingosine (obtained through the catalytichydrogenation of the sphingosine C₁₈); 2.24 g of dihydrolysergic acid;2.24 g of 1-hydroxybenzotriazole; and 2.06 g ofdicyclohexyl-carbodiimide. The reaction takes place in chloroform (130ml). The compound crystallizes from acetone, M.P. 200° C., yield 3.6 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:ammonia 1N (64:24:3.2), indicates that it is asingle compound with an Rf of 0.69.

Evaluation of the specific rotary power is carried out in a 2% methanolsolution using a 1 dm polarimetric tube. Results: (α)_(D) =-47.5°

Elementary analysis gives the following results (%):

C 73.61; H 10.22; N 7.45

For C₃₄ H₅₅ N₃ O₃ theoretical % calculated is

C 73.73; H 10.01; N 7.59

EXAMPLE 16 Product 16

Dihydrolysergylpsychosine amide of the formula ##STR28##

The procedure is carried out as described in Example 3, beginning with2.8 g of psychosine (obtained from the sphingolipids present in thebovine brain and containing a sphingosinic residue C₁₈); 1.62 g ofdihydrolysergic acid; 1.62 g of 1-hydroxybenzotriazole; and 2.06 g ofdicyclohexylcarbodiimide. The reaction takes place in a chloroformsolution, 100 ml of chloroform. The compound crystallizes from ethylacetate, M.P. 140° C., yield 3.8 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bychloroform:methanol:ammonia 1N (64:24:3.2), indicates that it is asingle compound with an Rf of 0.43.

Evaluation of the specific rotary power is carried out in a 2% methanolsolution using a 1 dm polarimetric tube. Results: (α)_(D) =-32°

Elementary analysis gives the following results (%):

C 67.01; H 8.62; N 5.48

For C₄₀ H₆₃ N₃ O₈, theoretical % calculated is

C 67.29; H 8.89; N 5.89

EXAMPLE 17 Products 17.1 and 17.2

Isolysergylpsychosine amide of the formula ##STR29## andlysergylpsychosine amide of the formula ##STR30##

The procedure is carried out as described in Example 2, beginning with6.7 g of D-lysergic acid; 4.45 g of N-N'-carbonyldimidazole; 12.7 g ofpsychosine (taken from sphingolipids present in the bovine brain andcontaining a sphingosinic residue C₁₈). The reaction takes place in adimethylformamide solution of the same volume as described in Example 2.The residue is then chromatographically fractionated, separating the twocompounds: Product 17.1 and Product 17.2.

a. Product 17.1--isolysergyl psychosine amide, M.P. 97°-100° C.

Chromatography on silica gel using an eluent mixture formed bychloroform: methanol: ammonia 1M (64:24:3.2), indicates that it is asingle compound with Rf 0.76.

Evaluation of the specific rotary power is carried out in a 2% methanolsolution using a 1 dm polarimetric tube. Results: (α)_(D) =+143°

Elementary analysis gives the following results (%):

C 67.35; H 8.51; N 5.65

For C₄₀ H₆₁ N₃ O₈ theoretical % calculated is

C 677.48; H 8.64; N 5.90

b. Product 17.2--lysergylpsychosine amide, M.P. 122°-126° C.

Chromatography on silica gel using an eluent mixture formed bychloroform:methanol:ammonia 1M (64:24:3.2), indicates that it is asingle compound with an Rf of 0.59.

Evaluation of the specific rotary power is carried out in a 2% methanolsolution using a 1 dm polarimetric tube. Results: (α)_(D) =+2°

Elementary analysis gives the following results (%):

C 67.40; H 8.56; N 5.71

For C₄₀ H₆₁ N₃ O₈ theoretical % calculated is

C 67.48; H 8.64; N 5.90

EXAMPLE 18 Product 18

Isonicotinylsphingosine amide of the formula ##STR31## 5 g ofsphingosine (taken from the sphingolipids present in the bovine brainand corresponding to a sphingosine C₁₈) are treated with 500 ml absoluteethanol. To the solution, 5.5 g of the p-nitrophenylester ofisonicotinic acid (prepared according to: C.A. 59, 8708b (1963)) isadded. The same procedure as described in Example 5 is then followed.The residue crystallizes from acetonitrile, M.P. 116° C., yield 6.0 g.

Thin layer chromatography (silica gel) using an eluent mixture formed bymethylene chloride: ethyl acetate: methanol (70:30:15), indicates thatit is a single compound with an Rf of 0.49.

Elementary analysis gives the following results (%):

C 71.12; H 9.78; N 6.70

For C₂₄ H₄₀ N₂ O₃ theoretical % calculated is

C 71.24; H 9.97; N 6.92

PHARMACOLOGICAL PROPERTIES

The compounds described above in Examples 1, 2, 3, 15 and 16 were testedfor pharmacological activity. These compounds were tested both in vitroand in vivo in laboratory animals and proved to be capable of actingdirectly on the central nervous system.

Product 1 from Example 1--Gamma-aminobutyrylsphingosine amide a. invitro tests

Gamma-aminobutyric acid (GABA), NH₂ (CH₃)₃ --CO₂ H, is an endogenoussubstance and is biologically active due to interaction with a specificreceptor but is incapable, by itself, of penetrating the encephalicbarrier. Accordingly, GABA has been found to be active in vitro butrelatively inactive in vivo. The compounds of the present invention, onthe other hand, are active both in vitro and in vivo. To show thisactivity of the compounds of the present invention, in vitro testsmeasuring the binding levels of radioactive gamma-aminobutyric acid, ³H-GABA, on synaptic membranes of the rat cortex were carried outaccording to the method of Enna and Snyder (Enna, S. J. and Synder, S.H., Mol. Pharmacol. 13, 442-45300; (1977)).

Table I presents the results of these tests, expressed in percentage ofthe fixed active product, comparing the in vitro activity of Product 1with the activities of the individual components which compriseProduct 1. The results show that sphingosine alone exhibits nobiological activity while GABA alone exhibits activity comparable tothat of Product 1.

                  TABLE I                                                         ______________________________________                                        Product 1                                                                     Binding on rat cortex membranes                                                                          Product                                            Product utilized           bound %                                            ______________________________________                                        .sup.3 H--GABA 2.10.sup.-8 M       100                                        .sup.3 H--GABA 2.10.sup.-8 M                                                               +      GABA 10.sup.-8 M                                                                             90                                                      +      GABA 10.sup.-7 M                                                                             45                                                      +      GABA 10.sup.-6 M                                                                             25                                                      +      GABA 10.sup.-5 M                                                                             20                                                      +      GABA 10.sup.-4 M                                                                             20                                         .sup.3 H--GABA 2.10.sup.-8 M                                                               +      sphingosine 10.sup.-8 M                                                                      100                                                     +      sphingosine 10.sup.-7 M                                                                      100                                                     +      sphingosine 10.sup.-6 M                                                                      100                                                     +      sphingosine 10.sup.-5 M                                                                      100                                                     +      sphingosine 10.sup.-4 M                                                                      100                                        .sup.3 H--GABA 2.10.sup.-8 M                                                               +      product 1 10.sup.-8 M                                                                        95                                                      +      product 1 10.sup.-7 M                                                                        60                                                      +      product 1 10.sup.-6 M                                                                        40                                                      +      product 1 10.sup.-5 M                                                                        25                                                      +      product 1 10.sup.- 4 M                                                                       20                                         ______________________________________                                    

b. in vivo tests

The in vivo activity of Product 1 was measured by the method describedby Costa et al (E. Costa, A. Guidotti and C. C. Mao; "Evidence forinvolvement of GABA in the Action of Benzodiazepines: Studies in RatCerebellum" in Mechanism of Action of Benzodiazepines; Ed. by E. Costaand P. Greengard, New York, Raven Press. pp. 113-130 (1975)) and byLoescher and Frey (Loesher, W. and Frey, H. H.; "Effect of convulsantand anticonvulsant agents on level and metabolism of gamma-aminobutyricacid in mouse brain"; Naunyn-Schmiedeberg's Arch. Pharmacol. 296,263-269 (1977)). These tests are based on the known activity ofisoniazide to cause convulsions and a lowering of the GABA cerebrallevels and the glutamicdecarboxylase enzyme activity. According to thetest method, isoniazide is administered to the control animals (rats)while isoniazide and the appropriate test compound are administered tothe groups of test animals and the results are measured in terms of thenumber of animals exhibiting convulsions, the latency of convulsions andthe number of deaths. The results are presented in Table II and showthat Product 1 has far superior in vivo activity as compared to GABA orsphingosine alone.

                  TABLE II                                                        ______________________________________                                        Product 1                                                                     Anticonvulsivant effects in rat                                                             Isoniazide                                                                              Isoniazide                                                                              Isoniazide                                                160 mg/kg 160 mg/kg 160 mg/kg                                                 (s.c.) ÷                                                                            (s.c.) +  (s.c.) +                                    Isoniazide    GABA      Sphingosine                                                                             Product 1                                   160 mg/kg     8 mg/kg   12 mg/kg  20 mg/kg                                    (s.c.)        (i.p.)    (i.p.)    (i.p.)                                      ______________________________________                                        Number of                                                                             26/30     24/30     20/30   9/30                                      animals in                                                                    convulsions                                                                   Latency of                                                                            3070 ± 110                                                                           3100 ± 156                                                                           3700 ± 200                                                                         4500 ± 330                             the convul-                                                                   sions meas-                                                                   ured in                                                                       seconds                                                                       Number of                                                                             15        14        9       3                                         dead ani-                                                                     mals                                                                          ______________________________________                                    

Product 3 of Example 3--Dihydrolysergylsphingosine amide a. in vitrotests

The in vitro biological activity was determined by comparative testsmeasuring the binding power of the labelled spiroperidole (³H)-spiroperidole on hypophysis sinaptosomal rat membranes according tothe method described by Greese et al (GREESE I., SCHNEIDER R. and SNYDERS. H.; H-spiroperidole labels dopamine receptors in pituitary and brain;Europ. J. Pharmacol. 46, 377-381 (1977)).

The results obtained and illustrated in Table III show that the bindingpower of Product 3 is significant and far superior, under the sameexperimental conditions, to that of dihydrolysergic acid or sphingosinealone.

                  TABLE III                                                       ______________________________________                                        Product 3                                                                     Binding to hypophysis membranes of rat                                        Product utilized     Product bound %                                          ______________________________________                                        (.sup.3 H) spiroperidole 2.10.sup.-9 M                                                                      100                                             (Control)                                                                     (.sup.3 H) spiroperidole 2.10.sup.-9 M +                                                           10.sup.-7 M                                                                            100                                             dihydrolysergic acid 10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                             95                                                                  10.sup.-4 M                                                                             45                                             (.sup.3 H) spiroperidole 2.10.sup.-9 M +                                                           10.sup.-7 M                                                                            100                                             sphingosine          10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                            100                                                                  10.sup.-4 M                                                                            100                                             (.sup.3 H) spiroperidole 2.10.sup.-9 M +                                                           10.sup.-7 M                                                                            100                                             Product 3            10.sup.-6 M                                                                             90                                                                  10.sup.-5 M                                                                             40                                                                  10.sup.-4 M                                                                             10                                             ______________________________________                                    

b. in vivo tests

The in vivo biological activity of Product 3 was measured by evaluatingthe serum levels of prolactin in hyperprolactinemic animals according tothe RIA method (radioimmunoassay) and the instructions in the NIAMDDprogram. The results obtained and illustrated in Table IV, expressed as% of inhibition, show that Product 3 exhibits significant biologicalactivity, especially as compared to the weak effect of dihydrolysergicacid.

                  TABLE IV                                                        ______________________________________                                        Product 3                                                                     Hypoprolactinemic effect in rats                                                                Prolactin Inhibition                                        Product utilized  ng/ml     %                                                 ______________________________________                                        Control at the circadian                                                                        68.0 ± 5.4                                                                           0                                                 peak at 4 p.m.                                                                Dihydrolysergic acid                                                          0.5 mg/kg         60.0 ± 3.2                                                                           0                                                 5.0 mg/kg         51.0 ± 6.7                                                                           25                                                Sphingosine                                                                   0.5 mg/kg         71.0 ± 4.2                                                                           0                                                 5.0 mg/kg         62.0 ± 6.8                                                                           0                                                 Product 3                                                                     0.5 mg/kg         38.7 ± 4.7                                                                           42                                                5.0 mg/kg         32.2 ± 5.7                                                                           52                                                Control                                                                       Sulpiride 10 γ/kg                                                                         77.0 ± 9.0                                                                           0                                                 Sulpiride + Dihydro-                                                          lysergic acid                                                                 0.5 mg/kg         66.0 ± 2.8                                                                           0                                                 5.0 mg/kg         65.0 ± 4.6                                                                           0                                                 Sulpiride + sphingosine                                                       0.5 mg/kg         72.0 ± 4.5                                                                           0                                                 5.0 mg/kg         77.0 ± 8.7                                                                           0                                                 Sulpiride + product 3                                                         0.5 mg/kg         53.7 ± 8.5                                                                           30                                                5.0 mg/kg         31.2 ± 2.5                                                                           60                                                ______________________________________                                    

Product 15 of Example 15--Dihydrolysergyldihydrosphingosine amide

The in vitro biological activity and in vivo activities of Product 15were evaluated according to the same methods as used above for Product 3of Example 3.

The results obtained and presented in Tables V and VI show the in vitroand in vivo activities of Product 15 to be far superior to eitherdihydrolysergic acid or dihydrosphingosine alone.

                  TABLE V                                                         ______________________________________                                        Product 15                                                                    Binding to hypophysis membranes of rat                                        Product utilized   Product  bound %                                           ______________________________________                                        (.sup.3 H) spiroperidole 2 nM                                                                             100                                               (Control)                                                                     (.sup.3 H) spriroperidole 2 nM +                                                                 10.sup.-7 M                                                                            100                                               dihydrolysergic acid                                                                             10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                             95                                                                  10.sup.-4 M                                                                             45                                               (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               dihydrosphingosine 10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                            100                                                                  10.sup.-4 M                                                                            100                                               (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               Product 15         10.sup.-6 M                                                                             90                                                                  10.sup.-5 M                                                                             30                                                                  10.sup.-4 M                                                                             20                                               ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Product 15                                                                    Hypoprolactinemic effect in rat                                                                 Prolactin  Inhibition                                       Product utilized  ng/ml      %                                                ______________________________________                                        Control at the circadian                                                                        62.0 ± 3.8                                                                            0                                                peak at 4 p.m.                                                                Dihydrolysergic acid                                                          0.5 mg/kg         60.0 ± 4.1                                                                            0                                                5.0 mg/kg         48.0 ± 5.1                                                                            23                                               Dihydrosphingosine                                                            0.5 mg/kg         66.0 ± 4.2                                                                            0                                                5.0 mg/kg         60.0 ± 2.8                                                                            0                                                Product 15                                                                    0.5 mg/kg         40.0 ± 5.6                                                                            35                                               5.0 mg/kg         31.0 ± 3.4                                                                            50                                               Control                                                                       Sulpiride 10 γ/kg                                                                         85.0 ± 9.0                                                                            0                                                Sulpiride + Dihydro-                                                          lysergic acid                                                                 10 γ/kg + 0.5 mg/kg                                                                       77.0 ± 5.0                                                                            0                                                10 γ/kg + 5.0 mg/kg                                                                       76.0 ± 8.0                                                                            0                                                Sulpiride + dihydrosphin-                                                     gosine                                                                        10 γ/kg + 0.5 mg/kg                                                                        81.0 ± 11.0                                                                          0                                                10 γ/kg + 5.0 mg/kg                                                                       74.0 ± 6.0                                                                            0                                                Sulpiride + product 15                                                        10 γ/kg + 0.5 mg/kg                                                                       48.0 ± 4.0                                                                            44                                               10 γ/kg + 5.0 mg/kg                                                                       39.0 ± 6.0                                                                            55                                               ______________________________________                                    

Product 2.2 of Example 2--Lysergylsphingosine amide

The in vitro and in vivo biological activities of Product 2.2 wereevaluated according to the same methods as described above for Product3, Example 3.

The results obtained and presented in Tables VII and VIII show the invitro and in vivo activities of Product 2.2 to be far superior to eitherlysergic acid or sphingosine alone.

                  TABLE VII                                                       ______________________________________                                        Product 2.2                                                                   Binding to hypophysis membranes of rats                                       Product utilized   Product  bound %                                           ______________________________________                                        (.sup.3 H) spiroperidole 2 nM                                                                             100                                               (Control)                                                                     (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               lysergic acid      10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                             90                                                                  10.sup.-4 M                                                                             60                                               (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               sphingosine        10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                            100                                                                  10.sup.-4 M                                                                            100                                               (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               product 2.2        10.sup.-6 M                                                                             85                                                                  10.sup.-5 M                                                                             55                                                                  10.sup.-4 M                                                                             35                                               ______________________________________                                    

                  TABLE VIII                                                      ______________________________________                                        Product 2.2                                                                   Hypoprolactinemic effect in rats                                                                Prolactin  Inhibition                                       Product utilized  ng/ml      %                                                ______________________________________                                        Control at the circadian                                                                        65.0 ± 4.8                                                                             0                                               peak at 4 p.m.                                                                Lysergic acid                                                                 0.5 mg/kg         61.0 ± 3.8                                                                             0                                               5.0 mg/kg         52.0 ± 6.2                                                                            20                                               Sphingosine                                                                   0.5 mg/kg         68.0 ± 6.0                                                                             0                                               5.0 mg/kg         61.0 ± 8.0                                                                             0                                               Product 2.2                                                                   0.5 mg/kg         48.0 ± 4.8                                                                            27                                               5.0 mg/kg         40.0 ± 2.6                                                                            39                                               Control                                                                       Sulpiride 10 γ/kg                                                                         87.0 ± 8.7                                                                             0                                               Sulpiride + Lysergic acid                                                     10 γ/kg + 0.5 mg/kg                                                                       76.0 ± 9.0                                                                            13                                               10 γ/kg + 5.0 mg/kg                                                                        73.0 ± 10.0                                                                          16                                               Sulpiride + Sphingosine                                                       10 γ/kg + 0.5 mg/kg                                                                        81.0 ± 11.0                                                                           0                                               10 γ/kg + 5.0 mg/kg                                                                       74.0 ± 6.0                                                                            14                                               Sulpiride + product 2.2                                                       10 γ/kg + 0.5 mg/kg                                                                       59.0 ± 6.0                                                                            32                                               10 γ/kg + 5.0 mg/kg                                                                       49.0 ± 5.0                                                                            44                                               ______________________________________                                    

Product 16 of Example 16--Dihydrolisergylpsychosine amide

The in vitro and in vivo biological activities of Product 16 wereevaluated according to the same methods as described for Product 3,Example 3.

The results obtained and presented in Tables IX and X show the in vitroand in vivo activities of Product 16 to be far superior to eitherdihydrolysergic acid or psychosine alone.

                  TABLE IX                                                        ______________________________________                                        Product 16                                                                    Binding to hypophysis membranes of rats                                       Product utilized   Product  bound %                                           ______________________________________                                        (.sup.3 H) spiroperidole 2 nM                                                                             100                                               (Control)                                                                     (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               dihydrolysergic acid                                                                             10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                            90                                                                   10.sup.-4 M                                                                            60                                                (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               psychosine         10.sup.-6 M                                                                            100                                                                  10.sup.-5 M                                                                            90                                                                   10.sup.-4 M                                                                            60                                                (.sup.3 H) spiroperidole 2 nM +                                                                  10.sup.-7 M                                                                            100                                               product 16         10.sup.-6 M                                                                            80                                                                   10.sup.-5 M                                                                            45                                                                   10.sup.-4 M                                                                            25                                                ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        Product 16                                                                    Hypoprolactinemic effect in rats                                                                Prolactin Inhibition                                        Product utilized  ng/ml     %                                                 ______________________________________                                        Control at the circadian                                                                        58.0 ± 6.0                                                                            0                                                peak at 4 p.m.                                                                Dihydrolysergic acid                                                          0.5 mg/kg         57.0 ± 5.0                                                                            0                                                5.0 mg/kg         49.0 ± 6.0                                                                           16                                                Psychosine                                                                    0.5 mg/kg         50.0 ± 5.0                                                                           14                                                5.0 mg/kg         41.0 ± 5.0                                                                           30                                                Product 16                                                                    0.5 mg/kg         40.0 ± 7.0                                                                           31                                                5.0 mg/kg         31.0 ± 6.0                                                                           47                                                Control                                                                       Sulpiride 10 γ/kg                                                                         81.0 ± 9.0                                                                            0                                                Sulpiride + Dihydro-                                                          lysergic acid                                                                 10 γ/kg + 0.5 mg/kg                                                                       77.0 ± 6.0                                                                            0                                                10 γ/kg + 5.0 mg/kg                                                                       70.0 ± 4.0                                                                           14                                                Sulpiride + psychosine                                                        10 γ/kg + 0.5 mg/kg                                                                       70.0 ± 6.0                                                                           14                                                10 γ/kg + 5.0 mg/kg                                                                       61.0 ± 7.0                                                                           25                                                Sulpiride + product 16                                                        10 γ/kg + 0.5 mg/kg                                                                       51.0 ± 7.0                                                                           37                                                10 γ/kg + 5.0 mg/kg                                                                       39.0 ± 4.0                                                                           52                                                ______________________________________                                    

THERAPEUTIC USES

According to the present invention, the organic amides derived fromnitrogenous lipids can be used as medicaments for various therapeuticuses, in particular for those uses corresponding to the activities ofthe active acids from which the amides are prepared. For example,derivatives of lysergic, isolysergic, dihydrolysergic, 2-bromo-lysergic,2-bromo-dihydrolysergic, 1-methyl-lysergic, 1-methyl-dihydrolysergic,1-methyl-2-bromo-lysergic, 1-methyl-2-bromo-dihydrolysergic,gamma-amino-butyric, valproic, trimethoxybenzoic and nicotinic acid aresuitable for use as medicaments capable of exhibiting pharmacologicalactivity on the central nervous system (CNS). The derivatives oflysergic acid, 2-bromo-lysergic, 1-methyl-lysergic and1-methyl-2-bromo-lysergic also exert a significant activity on theuterus. Specifically, the compounds of the present invention which areexperimentally active against isoniazid convulsions and on the bindingof GABA in vitro, and the pharmaceutical compositions containing them,may be therapeutically useful in pathologies connected with changes inthe function of the GABAurgic system, since these products are able toenhance levels of GABA in the central nervous system (CNS) and in thespecific cerebral areas, thereby enabling the GABA, bound to naturalamino-alcohols, to penetrate the blood-brain barrier. To be moreprecise, these compounds and the pharmaceutical preparations containingthem may be usefully employed in the prevention of convulsive stateswhich usually give rise to tonoclonic contractions and/or loss ofconsciousness, as in epilepsy; that is, in focal epilepsy, inpsychomotorial epilepsy, in major epilepsy, in idiopahtic epilepsy, instatus epilipticus and in centroencaphalic epilepsy (in minor epilepsy,akinetic attacks, mioclonic epilepsy) and in general, in pathologiesderiving from decrease of inhibitory control in the CNS.

The compounds which have proved to be active in inhibiting the serumlevels of prolactin and in the binding in vitro of the dopaminergicligand in the hypophysis, and the pharmaceutical compositions derivingfrom them, as exemplified in the in vivo and in vitro data noted above,may be usefully employed in pathologies which present alterations in therelease of neuropeptides from hypophysis as prolactin due to changes inthe regulation of the neurotransmittor systems with loss of dopaminergicsystem tonic inhibition or, in general, of the hypothalamic routes as inhyperprolactinemias caused by neuroleptics such as sulpiride,chlorpromazine, etc.

Thus, the drugs deriving from the compounds of the present invention maybe used in the treatment of behavioral alterations resulting frommodifications of neuropeptide hormones from hypophysis ashyperprolactinemic syndromes with loss of lipids and impotence, andhypopituitarism with changes in personality, apathy, indifference,astenia, loss of libido and confusion, and premenstrual syndromes withdepression and changes of mood and climacteric syndromes with variationsin mood, irritability, anxiety, nervousness and depression.

The compounds of the present invention can be administered aspharmaceutical compositions containing, as an active ingredient, one ormore of the amides in association with one or more compatible andpharmaceutically acceptable excipients. The compositions can beadministered via various administration routes, such as injectablesolutions, tablets, gelatine capsules and suppositories. The dosageadministered will vary depending upon the desired effect andadministration route, but, for example, in oral administration thedosages can be between 10 and 300 mg of active substance per day with asingle dosage of from 10 to 100 mg.

The following are examples of pharmaceutical compositions for oraladministration:

a. Pharmaceutical preparation 1: 10 mg tablets

Each tablet contains:

Active substance: 10 mg

Microcrystalline cellulose: 100 mg

Lactose: 150 mg

Magnesium stearate: 2.5 mg

Starch: 20 mg

b. Pharmaceutical preparation 2: 50 mg tablets

Each tablet contains:

Active substance: 50 mg

Microcrystalline cellulose: 100 mg

Lactose: 110 mg

Magnesium stearate: 2.5 mg

Starch: 20 mg

c. Pharmaceutical preparation 3: 100 mg tablets

Each tablet contains:

Active substance: 100 mg

Microcrystalline cellulose: 100 mg

Lactose: 2.5 mg

Magnesium stearate: 3.5 mg

Starch: 25 mg

d. Pharmaceutical preparation 4: 10 mg gelatine capsule

Each capsule contains:

Active substance: 10 mg

Vegetable oil: 100 mg

Gelatine: 100 mg

Glycerine: 25 mg

e. Pharmaceutical preparation 5: 50 mg gelatine capsule

Each capsule contains:

Active substance: 50 mg

Vegetable oil: 120 mg

Gelatine: 110 mg

Glycerine: 30 mg

f. Pharmaceutical preparation 6: 100 mg gelatine capsule

Each capsule contains:

Active substance: 100 mg

Vegetable oil: 150 mg

Gelatine: 130 mg

Glycerine: 44 mg

We claim:
 1. An organic amide compound of the formula: ##STR32## whereinR₁ --CO is a residue of a carboxylic acid which has biological orpharmaceutical activity, with the proviso that the carboxylic acid isnot a natural fatty acid normally bound to nitrogen of nitrogenouslipids, R₂ is a hydrogen atom, a saturated C₁₋₇ alkyl group or asaturated C₄₋₇ cycloalkyl group, and R₃ N is a residue of a phospholipidor sphingolipid, or a pharmaceutically acceptable salt thereof.
 2. Anorganic amide compound of the formula: ##STR33## wherein R₁ --CO is anacyl residue or theophyllineacetic acid, R₂ is a hydrogen atom and R₃ isa residue of a phospholipid having the chemical structure: ##STR34##wherein R and R' each represent a hydrogen atom or an acyl residue of amember selected from the group consisting of stearic, palmitic, oleic,linolenic, linoleic and arachidonic acid, or a pharmaceuticallyacceptable salt thereof.
 3. An organic amide compound of the formula:##STR35## wherein R₁ --CO is an acyl residue of theophyllineacetic acid,R₂ is a hydrogen atom and R₃ is a residue of a phospholipid having thechemical structure: ##STR36## wherein R and R' each represent a hydrogenatom or an acyl residue of a member selected from the group consistingof stearic, palmitic, oleic, linolenic, linoleic and arachidonic acid,or a pharmaceutically acceptable salt thereof.
 4. An organic amidecompound of the formula: ##STR37## wherein R₁ --CO is an acyl residue ofa theophyllineacetic acid, R₂ is a hydrogen atom and R₃ is a residue ofa sphingolipid having a chemical structure selected from the groupconsisting of: ##STR38## wherein n is from 6 to 16, ##STR39## wherein nis from 8 to 18, ##STR40## wherein n is from 6 to 16, ##STR41## whereinn is from 8 to 18, ##STR42## wherein n is from 6 to 16, ##STR43##wherein n is from 8 to 18, and ##STR44## wherein n is from 11 to 15, ora pharmaceutically acceptable salt thereof.
 5. An organic amide compoundaccording to claim 4, wherein R₃ represents the residue of asphingolipid having the chemical structure: ##STR45## wherein n is from6 to
 16. 6. An organic amide compound according to claim 4, wherein R₃represents the residue of a sphingolipid having the chemical structure:##STR46## wherein n is from 8 to
 18. 7. An organic amide compoundaccording to claim 4, wherein R₃ represents the residue of asphingolipid having the chemical structure: ##STR47## wherein n is from6 to
 16. 8. An organic amide compound according to claim 4, wherein R₃represents the residue of a sphingolipid having the chemical structure:##STR48## wherein n is from 8 to
 18. 9. An organic amide compoundaccording to claim 4, wherein R₃ represents the residue of asphingolipid having the chemical structure: ##STR49## wherein n is from6 to
 16. 10. An organic amide compound according to claim 4, wherein R₃represents the residue of a sphingolipid having the chemical structure:##STR50## wherein n is from 8 to
 18. 11. An organic amide compoundaccording to claim 4, wherein R₃ represents the residue of asphingolipid having the chemical structure: ##STR51## wherein n is from11 to
 15. 12. A pharmaceutical composition useful for treating disordersof the central and peripheral nervous systems comprising an effectiveamount of an organic amide compound according to claim 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier or diluent.
 13. Apharmaceutical composition according to claim 12, wherein saidcomposition is in oral dosage form containing from 10 to 100 mg. of saidorganic amide compound.